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EP2240195A1 - Traitement d'un mélanome avec des peptides d'alpha-thymosine en association avec des anticorps contre l'antigène 4 associé au lymphocyte t cytotoxique (ctla4) - Google Patents

Traitement d'un mélanome avec des peptides d'alpha-thymosine en association avec des anticorps contre l'antigène 4 associé au lymphocyte t cytotoxique (ctla4)

Info

Publication number
EP2240195A1
EP2240195A1 EP08859253A EP08859253A EP2240195A1 EP 2240195 A1 EP2240195 A1 EP 2240195A1 EP 08859253 A EP08859253 A EP 08859253A EP 08859253 A EP08859253 A EP 08859253A EP 2240195 A1 EP2240195 A1 EP 2240195A1
Authority
EP
European Patent Office
Prior art keywords
day
melanoma
dosage
ctla4
days
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08859253A
Other languages
German (de)
English (en)
Other versions
EP2240195A4 (fr
Inventor
Israel Rios
Cynthia W. Tuthill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sciclone Pharmaceuticals LLC
Original Assignee
Sciclone Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sciclone Pharmaceuticals LLC filed Critical Sciclone Pharmaceuticals LLC
Publication of EP2240195A1 publication Critical patent/EP2240195A1/fr
Publication of EP2240195A4 publication Critical patent/EP2240195A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2292—Thymosin; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • the present invention relates to the field of melanoma treatment.
  • Melanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in bowel and the eye (uveal melanoma). It is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths.
  • the treatment includes surgical removal of the tumor; adjuvant treatment; chemo- and immunotherapy, or radiation therapy. Of particular danger are metastases of the primary melanoma tumor.
  • a method of treating melanoma or a metastasis thereof in a human patient is a combination therapy which comprises administering a melanoma-treating combination to a human melanoma patient during a treatment regimen, the combination comprising an alpha thymosin peptide and antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA4).
  • CTLA4 cytotoxic T lymphocyte-associated antigen 4
  • the present invention is directed to a method of treating melanoma or metastases thereof in human patients.
  • the method involves administering a melanoma-treating effective combination to human melanoma patients, the combination comprising an alpha thymosin peptide and antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA4).
  • CTL4 cytotoxic T lymphocyte-associated antigen 4
  • the combination further includes one or more additional agents to combat or treat melanoma.
  • Alpha thymosin peptides comprise thymosin alpha 1 (TA1 ) peptides including naturally occurring TA1 as well as synthetic TA1 and recombinant TA1 having the amino acid sequence of naturally occurring TA1 , amino acid sequences substantially similar thereto, or an abbreviated sequence form thereof, and their biologically active analogs having substituted, deleted, elongated, replaced, or otherwise modified sequences which possess bioactivity substantially similar to that of TA1 , e.g., a TA1 derived peptide having sufficient amino acid homology with TA1 such that it functions in substantially the same way with substantially the same activity as TA1.
  • Suitable dosages of the alpha thymosin peptide can be within the range of about 0.001- 10mg/kg/day.
  • Thymosin alpha 1 and "TA 1” refer to peptides having the amino acid sequence disclosed in U.S. patent number 4,079,137, the disclosure of which is incorporated herein by reference.
  • Thymosin alpha 1 (TA1), initially isolated from Thymosin Fraction 5 (TF5), has been sequenced and chemically synthesized.
  • TA1 is a 28 amino acid peptide with a molecular weight of 3108.
  • Effective amounts of an alpha thymosin peptide are amounts which may be dosage units within a range corresponding to about 0.1-20 mg of TA1 , or about 1-10 mg of TA1 , or about 2-10 mg of TA1 , or about 2-7 mg of TA1.
  • the dosage unit may be within a range of 3-6.5 mg, and may comprise about 1.6, 3.2 or 6.4 mg of TA1 , or about 3.2 or about 6.4 mg of TA1.
  • a dosage unit may be administered once per day, or a plurality of times per day.
  • Melanoma has various stages, which may include Stage 0, I 1 II, III and IV, as well as their respective subdivisions.
  • the melanoma being treated is malignant metastatic melanoma.
  • the melanoma being treated is stage I, stage II, stage III or stage IV.
  • the melanoma being treated is stage M1a, M1 b or M1c melanoma.
  • dacarbazine (DTIC) is the conventional chemotherapeutic drug for the patients with melanoma.
  • the alpha thymosin peptide may be administered in a treatment regimen which includes administration to the patient of antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA4).
  • CTLA4 cytotoxic T lymphocyte-associated antigen 4
  • CTLA4 antibodies against cytotoxic T lymphocyte-associated antigen 4
  • CTLA4 include, without limitation, 9H10 (EBIOSCIENCE), MDX010 (MEDAREX), 1F4 (GENETEX), BNI3 (GENETEX), Q01 (ABNOVA), A01 (ABNOVA), M08 (ABNOVA), 1B8 (ABCAM), WKH203 (ABCAM), ab9984 (ABCAM), ab13486 (ABCAM), ipilimumab, ticilimumab or a combination thereof.
  • 9H10 is a functional-grade hamster anti-mouse antibody against CTLA-4 on T cells.
  • the method of the present invention may comprise administering the alpha thymosin peptide along with administering antibodies against cytotoxic T lymphocyte- associated antigen 4 (CTLA4), during a course of the treatment regimen.
  • CTLA4 antibodies may be administered concurrently with the alpha thymosin peptide or separately therefrom during the treatment regimen, e.g., on the same day(s) as the alpha thymosin peptide or on different days during the course of the treatment regimen.
  • the CTLA4 antibodies are administered in a dosage range of, e.g., 0.001-50 mg/kg patient body weight per day of administration, or about 0.01-20 mg/k, or about 1-15 mg/kg.
  • the combination further includes one or more additional agents to combat or treat melanoma.
  • additional agents may be antineoplastic agents such as alkylating antineoplastic agents (AIkAA), which include, without limitation, dacarbazine (DTIC).
  • AIkAA alkylating antineoplastic agents
  • DTIC dacarbazine
  • Additional agent(s) of the combination such as alkylating antineoplastic agents (AIkAA)
  • AIkAA may be administered to patient within a dosage range of, e.g., about 700-1300 mg/m 2 /day, more preferably in a dosage range of about 800-1200 mg/m 2 /day, and most preferably about 1000 mg/m 2 /day.
  • the various components of the combination may be administered concurrently with, or separately from, other components in a treatment regimen.
  • the treatment regimen comprises a plurality of days, with the alpha thymosin peptide comprising thymosin alpha 1 (TA1), and the TA1 being administered to the patient during at least a portion of the treatment regimen at a dosage within a range of about 0.5-10 mg/day.
  • the dosage is within a range of about 1.5-7 mg/day, or within a range of about 1.6-6.4 mg/day.
  • the dosage is within a range of 1.7-10 mg/day, or about 1.7-7 mg/day, or about 3-7 mg/day.
  • Exemplary dosages include 1.6, 3.2 and 6.4 mg/day.
  • the treatment regimen comprises administering the alpha thymosin peptide for a period of about 1-10 days, followed by about 1-5 days of non-administration of the alpha thymosin peptide.
  • the alpha thymosin peptide may be administered daily for about 3-5 days, followed by about 2-4 days of non-administration of the alpha thymosin peptide.
  • the alpha thymosin peptide may be administered daily for about 4 days, followed by about 3 days of non-administration of the alpha thymosin peptide.
  • the invention comprises use of an alpha thymosin peptide and CTLA4 antibodies in manufacture of a melanoma-treating effective pharmaceutical combination or medicament for use in a treatment regimen for treating melanoma or a metastasis thereof in a human melanoma patient.
  • said medicament is for use in a treatment regimen which substantially excludes any immune-stimulating cytokine to said patient during said treatment regimen in an amount significant for treatment of melanoma or a metastasis thereof.
  • said LDH blood level is below 475 IU/L.
  • said LDH blood level is between 100 - 335 IU/L.
  • One embodiment is the manufacture of a pharmaceutical combination including said alpha thymosin peptide, said combination further comprising CTLA4 antibodies for use during a course of the treatment regimen, which alpha thymosin peptide and CTLA4 antibodies may be administered separately or together.
  • said CTLA4 antibodies comprise ipilimumab.
  • said CTLA4 antibodies comprise ticilimumab.
  • said CTLA4 antibodies comprise 9H10.
  • said CTLA4 antibodies comprise MDX010.
  • said CTLA4 antibodies comprise Q01.
  • said CTLA4 antibodies comprise A01.
  • said CTLA4 antibodies comprise M08.
  • said CTLA4 antibodies comprise 1 B8.
  • said CTLA4 antibodies comprise WKH203.
  • said CTLA4 antibodies comprise ab9984.
  • said CTLA4 antibodies comprise ab 13486.
  • said medicament is for use in a treatment regimen which comprises a plurality of days, said alpha thymosin peptide comprises thymosin alpha 1 (TA1 ), and said TA1 is for use in administration to said patient during at least a portion of said treatment regimen at a dosage within a range of 0.5 - 10 mg/day.
  • said dosage is within a range of 1.5-7 mg/day.
  • said dosage is 3.2 mg/day.
  • said dosage is 6.4 mg/day.
  • said alpha thymosin peptide is TA1 and said medicament is for use in a treatment regimen which comprises administration of TA1 daily for a period of about 1-10 days, followed by about 1-5 days of non-administration of said TA1.
  • said TA1 is for use in administration daily for about 3-5 days, followed by about 2-4 days of non-administration of said TA1.
  • said TA1 is for use in administration daily for about 4 days, followed by about 3 days non-administration of said TA1.
  • C57BL/6 mice were implanted subcutaneously with murine B16 melanoma cells (Cell Culture Center, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences PUMC&CAMS, Beijing, P.R.China), followed by treatment with TA-1 or DTIC alone or in combination for 14 consecutive days.
  • the day of tumor implantation was defined as Day 0.
  • 9H10 was given in two groups via i.p. on Day 3, 6 and 9.
  • TA-1 and DTIC were administered daily by s.c. injection.
  • PBS Phosphate buffered saline
  • TA-1 was dissolved in PBS to achieve the proper dose concentration as indicated in Table 2.
  • TA-1 solution was stored at 2-8°C and used up in one week.
  • DTIC SIGMA
  • SIGMA DTIC
  • DTIC dosing solution was kept on ice, protected from light, and used within one day.
  • Final dosing solutions were prepared on the day of use by diluting the stock solution to 1 x with water.
  • the antibody reagent 9H10 (EBIOSCIENCE) was a ready-to- use agent at a concentration of 1 mg/mL.
  • TA-1 When used alone or in combination, TA-1 did not cause any loss of body weight throughout the course of the study, indicating that TA-1 was not toxic.
  • mice On Days 3 and 6 only a few mice had palpable tumors, and there was no statistical difference in tumor volume between vehicle control group and any treatment group. On Day 9, most mice of Group 1 (Vehicle Control), Group 2 (DTIC) and Group 3 (TA-1 ), and only a few of mice in Group 4 (9H10 + DTIC) and Group 5 (9H10 + DTIC + TA-1 ) had palpable tumors; the mean tumor volume of Groups 4 and 5 were statistically significantly smaller than Group 1 (p ⁇ 0.05). On Day 12 and Day 15, all mice in the Groups 1-5 showed palpable tumors, and the mean tumor volume of each drug treatment group except Group 2 (DTIC) was statistically significantly smaller than the vehicle control group (p ⁇ 0.05).
  • the percent inhibition (Pl) of TV (PITM) was calculated according to the equation below:
  • PITM (%) (TV vehicle - TVdrug treated )/ TV vehicle x 100
  • TW tumor weight
  • PITM, (%) 100 x (TW vehicle - TW drug treated)/ TW vehicle.
  • tumor weights were reduced by 43.35% in TA-1-only treated animals.
  • DTIC caused only a modest inhibition in tumor growth (e.g., 28.41%, based on tumor weight), while its combination with 9H10 increased tumor inhibition to 51.35%.
  • 9H10+DTIC was further combined with TA-1 , the tumor inhibition rate was further increased to 62.05%.
  • Example 2 (TA1 plus ipilimumab)
  • TA1 is administered as a combination therapy to Melanoma patients in treatment regimens at a dosage within a range of 0.5-10 mg/day.
  • Melanoma patients may be treated with intrapatient ipilimumab dose escalation until objective clinical response, ⁇ grade 3 autoimmunity or other dose limiting toxicity is reached.
  • Doses may start at 3 mg/kg in cohort I or 5 mg/kg in cohort II. Doses may be administered every 3 weeks, escalated to 5 mg/kg or 9 mg/kg every other dose and continued until response, adverse event, or disease progression on 9 mg/kg of antibody is seen.
  • TA1 is administered as a combination therapy to Melanoma patients in treatment regimens at a dosage within a range of 0.5-10 mg/day.
  • Ticilimumab is administered at single dose levels ranging from 0.01 to 15 mg/kg and/or at multiple dose levels ranging from 3 to 15 mg/kg.
  • the dosing regimens may include a single dose or multiple doses given, e.g., q1 month, q3 months, or the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Mycology (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Un mélanome ou une métastase de celui-ci est traité chez un patient humain par une thérapie d'association qui comprend l'administration d'une association de traitement de mélanome à un patient humain atteint d'un mélanome lors d'un schéma thérapeutique, l'association comprenant un peptide d'alpha-thymosine et des anticorps contre l'antigène 4 associé au lymphocyte T cytotoxique (CTLA4).
EP08859253A 2007-12-12 2008-12-08 Traitement d'un mélanome avec des peptides d'alpha-thymosine en association avec des anticorps contre l'antigène 4 associé au lymphocyte t cytotoxique (ctla4) Withdrawn EP2240195A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1310107P 2007-12-12 2007-12-12
PCT/US2008/013480 WO2009075813A1 (fr) 2007-12-12 2008-12-08 Traitement d'un mélanome avec des peptides d'alpha-thymosine en association avec des anticorps contre l'antigène 4 associé au lymphocyte t cytotoxique (ctla4)

Publications (2)

Publication Number Publication Date
EP2240195A1 true EP2240195A1 (fr) 2010-10-20
EP2240195A4 EP2240195A4 (fr) 2011-12-21

Family

ID=40755783

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08859253A Withdrawn EP2240195A4 (fr) 2007-12-12 2008-12-08 Traitement d'un mélanome avec des peptides d'alpha-thymosine en association avec des anticorps contre l'antigène 4 associé au lymphocyte t cytotoxique (ctla4)

Country Status (8)

Country Link
US (1) US20100330093A1 (fr)
EP (1) EP2240195A4 (fr)
JP (1) JP2011506436A (fr)
CN (1) CN101896190A (fr)
AR (1) AR069682A1 (fr)
AU (1) AU2008335840A1 (fr)
CA (1) CA2709027A1 (fr)
WO (1) WO2009075813A1 (fr)

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US20130296223A1 (en) * 2012-03-30 2013-11-07 Sciclone Pharmaceuticals, Inc. Use of thymosin alpha for the treatment of sepsis
WO2013177102A2 (fr) * 2012-05-21 2013-11-28 Felder Mitchell S Traitement du cancer par manipulation du système immunitaire
WO2016064969A1 (fr) * 2014-10-21 2016-04-28 Sciclone Pharmaceuticals, Inc. Traitement du cancer au moyen de stimulateurs immunitaires
US10806787B2 (en) 2015-02-16 2020-10-20 Pharma Foods International Co., Ltd. Anticancer agents or antimetastatic agents using FSTL1 and combination drug thereof
WO2017165778A1 (fr) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Procédés pour traiter des événements indésirables gastro-intestinaux d'origine immunitaire dans des traitements oncologiques immunitaires
WO2017165742A1 (fr) 2016-03-24 2017-09-28 Millennium Pharmaceuticals, Inc. Procédés de traitement d'événements indésirables liés à l'immunité gastro-intestinale dans des polythérapies anti-ctla4 et anti-pd-1
CN109793891A (zh) * 2017-11-17 2019-05-24 韩震 多肽化合物在制备提高治疗性抗体疗效的佐剂中的应用与组合物及其制备方法
IT201900016310A1 (it) * 2019-09-13 2021-03-13 Luigina Romani Timosina alfa 1 per l’uso nella prevenzione e nel trattamento degli effetti avversi immunitari correlati agli inibitori di checkpoint immunitari.

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DE2604845A1 (de) * 1976-02-07 1977-08-18 Knoll Ag Neue piperazinderivate
EP2633866A3 (fr) * 2003-10-17 2013-12-18 Novo Nordisk A/S Thérapie combinée

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FISCHKOFF S.A. ET AL.: "Durable response and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma.", J. CLIN. ONCOL., vol. 23, no. 16S (supplement), ABS.7525, June 2005 (2005-06), XP002662335, *
GARACI E ET AL: "Thymosin alpha 1 in the treatment of cancer: from basic research to clinical application", INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, vol. 22, no. 12, 1 December 2000 (2000-12-01), pages 1067-1076, XP002466383, ELMSFORD,NY, US ISSN: 0192-0561, DOI: 10.1016/S0192-0561(00)00075-8 *
See also references of WO2009075813A1 *

Also Published As

Publication number Publication date
US20100330093A1 (en) 2010-12-30
JP2011506436A (ja) 2011-03-03
WO2009075813A1 (fr) 2009-06-18
AR069682A1 (es) 2010-02-10
CN101896190A (zh) 2010-11-24
CA2709027A1 (fr) 2009-06-18
EP2240195A4 (fr) 2011-12-21
AU2008335840A1 (en) 2009-06-18

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